This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This application raises the possibility that diabetes is a disease process that negatively affects the growth reserve of the heart so that the enhanced cell death cannot be counteracted by repopulating cells that preserve the architecture and function of the myocardium. Previous studies show that diabetes leads to the activation of the renin-angiotensin system (RAS) which increases ROS generation and leads to myocyte hypertrophy and cell death. To test whether a similar sequence of events induces CPC senescence, we will examine how diabetes affects myocardial function in murine models of type 1 and type 2 diabetes and determine whether hyperglycemia activates RAS and it regulator p53. In addition, we will determine whether repopulating the diabetic heart with CPCs from non-diabetic hearts rescues the diabetic phenotype. These approaches represent a new view of cellular changes in the diabetic heart and may be able to identify a link between diabetes, ROS, premature CPC senescence, and heart failure, and may support the development of cell therapy for diabetic cardiomyopathy